Science —

Mapping the mutations of twelve major cancer types

Tumors from different tissues can have common genetic features.

Despite the gazillions of hours (and possibly as many dollars) spent searching for a cure for cancer, none has emerged. This is primarily because every tumor has a different mutational profile and therefore responds differently to treatment. The Cancer Genome Atlas is a consortium that was founded to use DNA sequencing to identify the most common, most significant mutations in cancers.

Ideally, this project will uncover new diagnostic markers and find new drug targets so we can achieve truly individualized medicine. In a paper that my thesis advisor would probably deride as “not hypothesis-driven,” they describe their analysis of 3,281 tumors from twelve different types of cancers, including breast, lung, colon, and ovarian carcinomas, as well as acute myeloid leukemia. The paper is in Nature (my boss would approve of that).

They analyzed 617,354 mutations, and found that 127 genes were significantly mutated. Many of the mutations occurred in genes that were previously known to be important in cancer, such as those encoding proteins that patrol for and prevent DNA damage and those that mobilize the cell’s response to various growth factors. But others were in cellular pathways not yet recognized as being vital in tumorigenesis. These included transcription factors, RNA splicing factors, and modifiers of histones, proteins responsible for maintaining the structural integrity of DNA.

Ninety three percent of the tumors analyzed had at least one mutation in at least one of these 127 genes but none had more than six mutated genes. The authors thus deduced that the number of cancer related genes (127) and the number of mutations required for oncogenesis (1-6) are both pretty small. However, this study looked only at nucleotide substitutions and small insertion/deletion mutants, and didn't look at large chromosomal rearrangements.

The most frequently mutated genes is that encoding… (drumroll, please): p53, Science magazine’s molecule of the year in 1993. Mutations in p53 were found in 42 percent of samples, and it was the most highly mutated gene in five of the cancer types they looked at. p53’s job is to scan along the length of DNA, looking for damage and instigating the proper repair machinery if any is found. So, that discovery should surprise no one.

A long standing puzzle in cancer research has been why mutations in a particular gene cause cancers in a specific tissue type and not others. Thus, some of the most interesting findings concern how different mutations cluster. For example, the work identified five distinct breast cancer clusters, each driven by mutations in a different gene. 69.8 percent of head and neck squamous cell carcinomas had mutant p53, like 94.6 percent of ovarian cancers and one of the breast cancer clusters.

Although these tumor types might not initially appear to be similar, perhaps their underlying genetic similarity means that they will respond to similar therapeutics. Mutations in two well- studied cancer genes, APC and KRAS, were detected “almost exclusively” in colon and rectal carcinoma. Lung cancers didn’t have any identifiable clusters; collectively, the tumors had mutations in many of the 127 genes.

Mutations in fourteen genes were found to be mutually exclusive in certain cancers (no tumors had both), and 148 pairs were found to consistently occur together. A higher rate of variability in a mutated gene—so more mutations in it—was taken to mean that the gene was mutated early on in tumorigenesis (looking at you again, p53). A lower rate of variability suggests that the gene plays a role in the progression, rather than formation, of the tumor.

The authors note that the analysis of this and similar genomic data can give “reasonable chances of identifying the ‘core’ cancer genes and pathways and tumor-type-specific genes and pathways in the near term.” Hopefully, common therapeutic strategies might be applied to tumors that are found to be similar genetically, even if they appear different or arise in different tissues.

My instinct (no science here) is that cancer is one of Nature's means to help evolve the species. What's that old saying? What doesn't kill you, makes you stronger? Disease has always carried off the physically weaker of the species, and I think that it has other ramifications as well. It helps keep the gene pool clean (and evolving), and keeps the population in more manageable numbers. Our obsession with fighting disease, while good in the short term, may doom us in the longer term.

As said, this is TOTALLY unscientific, and just my instinctual take on this situation. Any resemblance to reality is totally unintended! :-)

This article jumped out at me immediately after I saw leukemia . I was diagnosed with it on September 21st. I have just finished my 1st round of chemotherapy and 1 month in the hospital. Its possible I will need 2 more round of chemo. I handled its really well considering. The 1st is the worst apparently. My friend died of it 10 years ago but apparently now there is and 80% survival rate and I'm still pretty young.

Cancer often manifests well after reproduction has occurred, and when it occurs earlier is often extraordinarily malignant and kills BEFORE reproduction without aggressive medical and/or surgical management. So it is not nature's way of doing anything.

This article jumped out at me immediately after I saw leukemia . I was diagnosed with it on September 21st. I have just finished my 1st round of chemotherapy and 1 month in the hospital. Its possible I will need 2 more round of chemo. I handled its really well considering. The 1st is the worst apparently. My friend died of it 10 years ago but apparently now there is and 80% survival rate and I'm still pretty young.

Best wishes to you, hope one round was enough. (I had 6 rounds for a different type and first was the worst in my case as well).

My instinct (no science here) is that cancer is one of Nature's means to help evolve the species. What's that old saying? What doesn't kill you, makes you stronger? Disease has always carried off the physically weaker of the species, and I think that it has other ramifications as well. It helps keep the gene pool clean (and evolving), and keeps the population in more manageable numbers. Our obsession with fighting disease, while good in the short term, may doom us in the longer term.

As said, this is TOTALLY unscientific, and just my instinctual take on this situation. Any resemblance to reality is totally unintended! :-)

No, nonfatal mutations help evolve the species. That which kills you, e.g. cancer, makes you dead.

My instinct (no science here) is that cancer is one of Nature's means to help evolve the species. What's that old saying? What doesn't kill you, makes you stronger? Disease has always carried off the physically weaker of the species, and I think that it has other ramifications as well. It helps keep the gene pool clean (and evolving), and keeps the population in more manageable numbers. Our obsession with fighting disease, while good in the short term, may doom us in the longer term.

As said, this is TOTALLY unscientific, and just my instinctual take on this situation. Any resemblance to reality is totally unintended! :-)

I have to agree with Shavano here. The only kinds of mutations that can make a *species* stronger have to occur in the zygote of a forming infant so that the mutation has the ability to be passed on to future offspring. (The reproductive cell germline splits off of the rest of the organism's stem-cell pool early in development, meaning the mutation would have to occur before that split to be able to be passed on.) Altogether, this means that mutations that occur late in life, in a subset of all of an organisms cells, cannot affect the rest of the species and only affect the individual. The fact that most cancers become evident after reproductive age also limits how cancer can affect gene selection. Worse, some genes, like the BRCA1 and BRCA2, exhibit pleiotropic effects on individuals carrying the mutant copies, effects that could favor reproduction early in life and go on to cause cancer later in life.

"Disease has always carried off the physically weaker of the species," is far too broad a simplification of a relatively complicated system of genes, mutations, and selective pressures.

I guess that in a primitive society cancer would ultimately move evolution forward. However it wouldn't be because people survived it, rather the people with less disposition to getting it would be more likely to have more children.

Cancer is caused by mutations that - when combined - cause cells to become malignant. This end point clearly isn't evolution, but perhaps it could be argued that some of the mechanisms that cause initial mutations are.

Bacteria are known to have specific enzymes that force mutation when they are under duress. Many don't make it, but those that do may pick up vital genes that 'evolve' them.

If there is a similar mechanism in certain human tissues that deliberately ramp up mutation then maybe that could be considered a driving force for evolution?

If I'm understanding this right, they're finding related random mutations, not inheritable tendencies... With that in mind, I suspect people's urge to point to evolution is related to the old belief that if you do everything "right" then you're safe from cancer. Since "I did X, Y and Z so I'm safe" obviously ignores too many cases to seem scientific, some people turn to "it's evolutionary pressure, but I'm healthy and don't have relatives that died young of cancer, so I'm safe."

If I'm understanding this right, they're finding related random mutations, not inheritable tendencies... With that in mind, I suspect people's urge to point to evolution is related to the old belief that if you do everything "right" then you're safe from cancer. Since "I did X, Y and Z so I'm safe" obviously ignores too many cases to seem scientific, some people turn to "it's evolutionary pressure, but I'm healthy and don't have relatives that died young of cancer, so I'm safe."

Your body has many avenues for fighting off cancer - yep, cancer cells arise in all of us, and most of the time our body just takes out the trash. Just like everything else, those mechanisms and their efficacy can be dictated by genetics.

Similarly you can have inherited genetic traits which make it more likely that cancerous mutations will arise by chance.

This article jumped out at me immediately after I saw leukemia . I was diagnosed with it on September 21st. I have just finished my 1st round of chemotherapy and 1 month in the hospital. Its possible I will need 2 more round of chemo. I handled its really well considering. The 1st is the worst apparently. My friend died of it 10 years ago but apparently now there is and 80% survival rate and I'm still pretty young.

I'm a big fan of Stephen Jay Gould generally but particularly his essay "The Median isn't the Message" which he wrote after being diagnosed with peritoneal mesothelioma in 1982:

How does one prevent that unless you live in a bubble, with no sunlight, toxic substances, virus, bacteria, etc.?

I really wish people would stop saying cancer research is trying to prevent cancer. There is no way to prevent cancer, only find better methods of diagnosis for quickly and efficiently combating it.

And why was it surprising that gene mutations for "encoding proteins that patrol for and prevent DNA damage" would be found when analyzing individual cancers? Isn't that literally a more likely cause of the cancer itself, if the cell has lost the ability to repair or validate it's own code?

This article made me so angry. We have known for 20+ years that cancer was caused by major genetic corruption, why are we wasting time building statistics still?

An odd way of putting it. Cancer is caused by mutations that allow uncontrolled cell growth. Mutating with oer phenotypes are possible, but tend not to be noticed. However, "corruption" in this context is not really a meaningful statement, because any mutation could be described as corrupting the original sequence

Quote:

This article made me so angry. We have known for 20+ years that cancer was caused by major genetic corruption, why are we wasting time building statistics still?

The problem was, and still is: how can tumor cells be treated without unduly harming the host. One approach is to characterize the types of mutations that occur; the paper being described in the this Ars post is one report on this effort.

Since this approach has been successful in at least some tumor types (e.g., HER/2neu breast cancer), I wonder: what is making you angry?

Is there a way to deliver p53 or other tumor suppressor proteins to cells on a prophylactic basis?

Normal cells have p53. Adding p53 genes to abnormal cells in a patient would require genetically modifying essentially all of the tumor cells, without triggering an immune response. This is probably not possible. Moreover, any approach that could specifically modify all of the tumor cells would be likely to be far more useful if the modification was to cause those cells to undergo apoptosis (a tidy form of cell suicide).

I guess that in a primitive society cancer would ultimately move evolution forward. However it wouldn't be because people survived it, rather the people with less disposition to getting it would be more likely to have more children.

And more likely to raise them to adulthood, since many cancers occur in middle age.

Cancer is caused by mutations that - when combined - cause cells to become malignant. This end point clearly isn't evolution, but perhaps it could be argued that some of the mechanisms that cause initial mutations are.

Bacteria are known to have specific enzymes that force mutation when they are under duress. Many don't make it, but those that do may pick up vital genes that 'evolve' them.

If there is a similar mechanism in certain human tissues that deliberately ramp up mutation then maybe that could be considered a driving force for evolution?

Not unless those certain tissues were testicles or ovaries. We get dozens of mutations per person per generation due to random copying errors and chemically induced as well as radiation-induced damage. Complex organisms such as people and fireflies wouldn't be possible without a mechanism built into each cell to identify and repair (usually right but sometimes not) similar damage in our somatic cells, nor would the transmission of a consistent body plan across many generations.

Cancer isn't some evolved response that enhances species viability. It's system failure.

Is there a way to deliver p53 or other tumor suppressor proteins to cells on a prophylactic basis?

Normal cells have p53. Adding p53 genes to abnormal cells in a patient would require genetically modifying essentially all of the tumor cells, without triggering an immune response. This is probably not possible. Moreover, any approach that could specifically modify all of the tumor cells would be likely to be far more useful if the modification was to cause those cells to undergo apoptosis (a tidy form of cell suicide).

Caillebotte, in the first suggestion I didn't mean the genes, I meant a wholesale administration of the tumor suppressor PROTEIN to all the cells in the body, not trying to differentiate between cancerous and non-cancerous cells.

I'm wondering if its possible to (1) get a protein like that through the cell and nuclear membranes, and (2) Whether a higher concentration of this protein in cells that have no problem expressing it wouldn't screw up the cell metabolism in some way.

Cancer is caused by mutations that - when combined - cause cells to become malignant. This end point clearly isn't evolution, but perhaps it could be argued that some of the mechanisms that cause initial mutations are.

Bacteria are known to have specific enzymes that force mutation when they are under duress. Many don't make it, but those that do may pick up vital genes that 'evolve' them.

If there is a similar mechanism in certain human tissues that deliberately ramp up mutation then maybe that could be considered a driving force for evolution?

Not unless those certain tissues were testicles or ovaries. We get dozens of mutations per person per generation due to random copying errors and chemically induced as well as radiation-induced damage. Complex organisms such as people and fireflies wouldn't be possible without a mechanism built into each cell to identify and repair (usually right but sometimes not) similar damage in our somatic cells, nor would the transmission of a consistent body plan across many generations.

Cancer isn't some evolved response that enhances species viability. It's system failure.

Not necessarily true.From a strict evolutionary standpoint there's a benefit for the species: By culling the non-reproducing population, cancer makes sure that there's plenty of resources for the new generations.Humans reach the age of reproduction around 12-16 years old, but the children need constant care until that age, meaning that the adults need to stay alive until 30-40 years old to ensure successful reproduction. After that age they are a resource burden. (Of course this line of thinking is only true for the pre-historic era, I'm not talking about modern societies, because they are outside the scope of evolution in this regard.).

Other factor to consider: Cancer/self-destruction of adults speeds up the changing of generations, which leads to faster evolution, faster selection of positive traits.

Of course this does not take into consideration that there are benefits for the society by keeping the old/not-reproducing people alive. But that's self-evident, as:1. evolution needs more time to select those groups that "chose" this path for survival, as opposed to a hypothetical spartan society.2. human species is somehow exempt from the driving force of evolution, as with the help of medicine we try to keep everyone alive, so natural selection cannot really select the best fit individuals. But then there's cultural evolution...

Thanks for this article, Diana. I think this is the only one that points out that we "didn't look at large chromosomal rearrangements". Or DNA methylation, RNA editing, mutations outside the exome, etc etc. Progress in baby steps.